In general, our purpose is to expand continuing and start new projects to study the factors responsible for abnormal responses of humans to drugs. Although our primary focus will be on environmental factors (prior and combined exposure to other chemical agents and physical agents such as temperature, pressure, or radiation), we will also look at inherent factors (disease states or pre-existing pathologic conditions, hormonal variations, immunologic, or genetic status, etc.). These studies will be performed at the clinical level utilizing animals to help explain the phenomenon seen in humans as well as to suggest possible approaches for such studies in humans. In addition to utilizing existing methods, efforts will be directed toward developing methods to quantitate drug action, absorption, distribution, and metabolism in the intact human. This will include adaptation of methods used in animals as well as development of new methods.